The present description relates generally to the field of small molecule inhibitors of protein kinase D, collectively called “pan-PKDs.” The protein kinase D (PKD) family of enzymes includes three closely related but distinct serine kinases, PKD1, PKD2 and PKD3. These three enzymes have a conserved N-terminal regulatory domain made of two cysteine rich diacylglycerol (DAG) binding motifs and an autoinhibitory pleckstrin homology (PH) domain, and a conserved C-terminal catalytic domain.
Enzymes of the PKD family are activated by signaling pathways involving the activation of gamma-phospholipase C, production of diacylglycerol and activation of protein kinase C enzymes. PKC-mediated phosphorylation of the two conserved serine residues in the catalytic domain appears to be essential for activation of PKD enzymes.
The PKD enzymes play an important role in various biological processes. For instance, PKD is implicated to play a role in lymphocyte biology, the regulation of Golgi organization in cell and in protein trafficking. It also has been proposed that PKD1 controls gene transcription via regulation of class II histone deacetylases in T-lymphocytes and cardiac cells. The role of PKD in various cellular processes such as angiogenesis, cell proliferation cellular hypertrophy, cell migration and invasion thus make members of this family of enzymes candidate therapeutic targets for the treatment of various disease conditions, including cancer, cardiac hypertrophy, and angiogenesis-related diseases.